The background to this invention U.S. Pat. No. 3,313,813 patented Apr. 11, 1967 and issued to Edward J. Cragoe, Jr., shows novel (3-amino-5,6-disubstituted-pyrazinoyl)guanidine compounds. The compounds of the U.S. Pat. No. 3,313,813 are useful because they possess diuretic and natriuretic properties. They differ from most of the known, effective diuretic agents, however, in that the compounds of U.S. Pat. No. 3,313,813 selectively enhance the excretion of sodium ions while simultaneously causing a decrease in excretion of potassium ions. The potassium loss, which is caused by known diuretics, often results in a severe muscular weakness. Since the compounds of the U.S. Pat. No. 3,313,813 prevent the potassium depletion, they have this decided advantage as diuretics. As diuretic agents, they can be used for the treatment of edema, hypertension and other diseases or conditions known to be responsive to this therapy and are especially useful when used in combination with or concomitantly with potassium losing diuretic agents.
Applicants' instant pyrazinecarboxamide compounds shown in Formula I subsequently differ from the compounds shown in U.S. Pat. No. 3,313,813, in that they have a guanylureido group (--N.dbd.C(NH.sub.2)NH--CONH.sub.2) or substituted guanylureido group in place of the guanidino group of the compounds in the stated U.S. Patent. Applicants have found that the guanylureido group changes the pharmaceutical action and utility of these compounds. It has been found in U.S. Pat. No. 3,313,813 that the pyrazinoylguanidine compounds therein described when co-administered with other diuretic agents known to enhance the elimination of potassium ions along with sodium ions, will maintain the potassium ion excretion at approximately the normal or control rate and thus overcome this undesirable property of other diuretic agents.
In actuality, applicants' compounds in the instant case as further described, accomplish the objective previously achieved by using a combination of the pyrazinoylguanidine compounds of U.S. Pat. No. 3,313,813 with diuretic agents which cause elimination of sodium with concomitant excessive potassium elimination. Thus, the effect of introducing a carboxamide group to the pyrazinoylguanidine compounds of U.S. Pat. No. 3,313,813 results in producing eukalemic saluretic agents. Since the compounds of the instant invention are thus eukalemic saluretic agents they constitute single entities which are useful for the treatment of edema and hypertension and other diseases or conditions known to be responsive to this therapy.